title: Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient-specific induced pluripotent stem cells.
abstract: Disease-specific induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity to establish novel disease models and accelerate drug development using distinct tissue target cells generated from isogenic iPSC lines with and without disease-causing mutations. To realize the potential of iPSCs in modeling acquired diseases which are usually heterogeneous, we have generated multiple iPSC lines including two lines that are JAK2-wild-type and four lines homozygous for JAK2-V617F somatic mutation from a single polycythemia vera (PV) patient blood. In vitro differentiation of the same patient-derived iPSC lines have demonstrated the differential contributions of their parental hematopoietic clones to the abnormal erythropoiesis including the formation of endogenous erythroid colonies. This iPSC approach thus may provide unique and valuable insights into the genetic events responsible for disease development. To examine the potential of iPSCs in drug testing, we generated isogenic hematopoietic progenitors and erythroblasts from the same iPSC lines derived from PV patients and normal donors. Their response to three clinical JAK inhibitors, INCB018424 (Ruxolitinib), TG101348 (SAR302503), and the more recent CYT387 was evaluated. All three drugs similarly inhibited erythropoiesis from normal and PV iPSC lines containing the wild-type JAK2 genotype, as well as those containing a homozygous or heterozygous JAK2-V617F activating mutation that showed increased erythropoiesis without a JAK inhibitor. However, the JAK inhibitors had less inhibitory effect on the self-renewal of CD34+ hematopoietic progenitors. The iPSC-mediated disease modeling thus underlies the ineffectiveness of the current JAK inhibitors and provides a modeling system to develop better targeted therapies for the JAK2 mutated hematopoiesis.
authors.affiliation: Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Ye
authors.forename: Cyndi F
authors.initials: CF
authors.lastname: Liu
authors.forename: Lucie
authors.initials: L
authors.lastname: Lanikova
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Dowey
authors.forename: Chaoxia
authors.initials: C
authors.lastname: He
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Huang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Spivak
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.forename: Linzhao
authors.initials: L
authors.lastname: Cheng
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D004900:Erythroblasts / Q000187:drug effects* / Q000201:enzymology; D004920:Erythropoiesis / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2
keywords: Erythropoiesis; Hematopoietic malignancies; Hematopoietic progenitor cells; Induced pluripotent stem cells; Preclinical drug evaluation